Abstract

Cancer stem cells (CSCs) are the pathological counterpart of normal somatic tissue stem cells. They possess the capacities
to self‐renew and to generate a more differentiated, rapidly dividing and expanding tumour progeny. Although they constitute
just a small percentage of the tumour mass, they are responsible for its maintenance and, therefore, they should be the target
of anticancer treatments. The existence of CSCs is still a matter of controversy for certain tumour types – some of which
are actually frequent and clinically relevant – but it is confirmed in many others. Moreover, CSCs are predictably genetically
diverse, and their frequency and phenotype can vary in the course of the disease. However, CSCs have nowadays been identified
in almost all the frequent types of tumours, and recent findings have shown that CSC gene expression signatures can be predictive
of adverse clinical outcome, therefore maintaining the study of CSCs at the forefront of cancer research.

Key Concepts:

Not all the cells within the tumour are equally capable of regenerating the tumour, either in transplantation experiments
or in patient's relapse after surgery and treatment.

Cancer stem cells (CSCs) are the only cells within the tumour with the capacity to maintain and regenerate the tumour, and
are responsible for cancer relapse.

Tumours are therefore stem cell‐maintained tissues, like many other tissues in the organism.

Understanding the biology of CSCs, their origin, evolution and molecular characteristics, should help us to design CSC‐specific
therapies that should complement current anticancer treatments, mainly aimed at the reduction of the tumour mass composed,
for the most part, of nonself‐renewing cells.

Keywords: stem cells; cancer; solid tumours; leukaemia; mouse models

Figure 1.

Traditional cancer theories versus CSC theory. (a) Traditional view of cancer as a disease of abnormal proliferation where cells divide in an uncontrolled fashion. Divisions are symmetrical, daughter cells are identical. According to this model, each cell in the tumour mass should be equally capable of regenerating a new tumour in an empty host. However, upon injection of a single tumour cell, although potentially initial engraftment might happen, experimentally there is neither cancer formation nor capability of serial transplantation unless a certain minimum number of cells are injected. This required number would be dependent on the percentage of CSCs present in the tumour of origin. (b) CSC theory. Cancer as a hierarchically organised tissue originated and maintained by CSCs. These cells can divide asymmetrically, giving rise to a new CSC maintaining stem properties and another transit‐amplifying cell with no stem potential but with high proliferative capacity. These cells will expand, differentiate to a certain extent and constitute the majority of the tumour mass. Cells from the differentiated pool lack the capacity to regenerate cancer in a new host. One single cell from the CSC pool is able to recapitulate all the tumour features and give rise to a complete tumour upon transplantation (even serialy). Upon injection of a certain number of nonpurified, nondiscriminated tumour cells, the tumour will only be transplanted if CSCs are injected in this mixture. The cells in the CSC pool can also divide symmetrically, giving rise to two new CSCs without necessarily having to contribute to the main tumour population.

Figure 2.

Origin of the CSCs. Within a hierarchically organised normal tissue, the acquisition by a given cell of the properties of a cancer stem cell can happen mainly via two possible mechanisms. (1) If the cancer‐inducing genetic defect occurs in a differentiated cell without stem properties, there are two possible scenarios, depending on the interactions between the cell phenotype and the new properties that the oncogenic mutations are able to confer. If the genetic defect cannot confer stem cell properties to the target cell, then there is no long‐term self‐renewal of the clone and no tumour will arise. If the genetic defect can, however, endow stem cell properties to the target cell, then a new functional CSC is generated that will give rise to a new tumour composed by a population of proliferating cells unable to terminally differentiate that is maintained by the CSC. (2) If the cancer‐inducing genetic defect occurs in a stem cell, then no additional requirements are needed, since the cell already possesses all the necessary capabilities to function as the stem cell of the tumour.

Figure 3.

Searching for CSC‐specific targets. To specifically destroy CSCs without having harmful side‐effects it is necessary to find molecular targets than can distinguish them from normal somatic tissue stem cells. One possible way to do this is to purify normal stem and CSC populations, both from human tumours or from CSC‐based animal models of cancer and to compare them at all the levels (genetic, epigenetic, transcriptional and translational profiles) and study the differences between them in order to find targets that can potentially serve for diagnosis, prognosis and/or treatment.